Our laboratory and others have proposed that neurodegeneration as a consequence of HIV-1 infection in the brain is predominantly dependent on the release of toxins by HIV-infected or gp120-activated microglia and macrophages. These toxins produce an excitotoxic injury via oxidative/nitrosative stress, and result in neuropathological changes, including dendritic injury, synaptic damage, and neuronal apoptosis. In attempting to prevent this type of HIV-related neurotoxicity, we discovered that erythropoietin (EPO), normally thought to be a kidney-generated cytokine, is made in the brain and is neuroprotective. Additionally, we and others found that insulin-like growth factor-I (IGF-I) is also neuroprotective. Here we report our preliminary data that EPO and IGF-I can prevent neuronal damage due to gp120 in a synergistic fashion in vitro, we demonstrate the likely molecular mechanism for this neuroprotective synergy, and we propose to study this effect in the HIV/gp 120-transgenic mouse as in vivo proof-of-principle to expedite human clinical trials with these clinically-tolerated agents. Specific Aims: 1. To assess the possible neuroprotective effect of EPO in the HIV/gp120 transgenic mouse model. Hypothesis Tested: EPO protects neurons from HIV-related neuronal damage via a phosphoinositide (PI) 3 kinase/Akt (protein kinase B)-mediated transduction pathway acting, at least in part, through glycogen synthase kinase 3beta (GSK3beta) to prevent the hyperphosphorylation of tan. In contrast to EPO, gp120 decreases Akt phosphorylation. 2. To assess the possible neuroprotective effect of IGF-I in the HIV/gp120 transgenic mouse model. Hypothesis Tested: IGF-I also protects neurons via the PI3 kinase/Akt-mediated transduction pathway acting, at least in part, through GSK3beta to prevent the hyperphosphorylation of tau. 3. To assess the possible synergistic neuroprotective effect of EPO+IGF-I in the HIV/gp120 transgenic mouse model. Hypothesis Tested: EPO+IGF-I act synergistically to activate the anti-apoptotic PI3 kinase/Akt signaling pathway, and thus provide a synergistic degree of neuroprotection.